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The Challenge of Diagnosis and Indication for Treatment in Fabry

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The Challenge of Diagnosis and Indication for Treatment in Fabry Original Article Journal of Inborn Errors of Metabolism & Screening 2017, Volume 5: 1–7 The Challenge of Diagnosis and Indication ª The Author(s) 2017 DOI: 10.1177/2326409816685735 for Treatment in Fabry Disease journals.sagepub.com/home/iem Marco A. Curiati, MD1, Carolina S. Aranda, MD, MSc1, Sandra O. Kyosen, MD, MSc1, Patricia Varela, MSc2, Vanessa G. Pereira, PhD3, Vania D’Almeida, PhD3, Joa˜o B. Pesquero, PhD2, and Ana M. Martins, MD, PhD1 Abstract Fabry disease, caused by deficient alpha-galactosidase A lysosomal enzyme activity, remains challenging to health-care professionals. Laboratory diagnosis in males is carried out by determination of alpha-galactosidase A activity; for females, enzymatic activity determination fails to detect the disease in about two-thirds of the patients, and only the identification of a pathogenic mutation in the GLA gene allows for a definite diagnosis. The hurdle to be overcome in this field is to determine whether a mutation that has never been described determines a ‘‘classic’’ or ‘‘nonclassic’’ phenotype, because this will have an impact on the decision-making for treatment initiation. Besides the enzymatic determination and GLA gene mutation determination, researchers are still searching for a good biomarker, and it seems that plasma lyso-Gb3 is a useful tool that correlates to the degree of substrate storage in organs. The ideal time for treatment initiation for children and nonclassic phenotype remains unclear. Keywords genotype-phenotype correlation, enzyme replacement therapy, alpha-galactosidase A deficiency, dried blood spot on filter paper, screening Introduction a normal range of values, as found in healthy individuals.1,2,5–7 In those patients, a diagnostic is performed with GLA gene Fabry disease (FD) is an X-linked lysosomal storage disorder molecular analysis. caused by deficiency of alpha-galactosidase A (a-gal A) activ- Molecular analysis of the GLA gene is an essential diag- ity involved in the degradation of glycosphingolipids. Its defi- nostic tool in women or in patients who have very strong ciency leads to the accumulation of globotriaosylceramide clinical suspicion due to the presented symptoms but (Gb3) inside the cells, causing several clinical abnormalities; the enzyme activity is within the normal range. Furthermore, the GLA gene is located on Xq22.1.1 it can inform the treating physician about the exact kind The clinical suspicion of FD begins with a selection of of mutation, which is generally related to the clinical characteristic signs and symptoms, such as acroparesthesia, angiokeratomas, recurring headache, abdominal pain, chronic diarrhea, progressive loss of renal function, cardiomyopathy 1 generally associated with myocardial fibrosis, central nervous Reference Center in Inborn Errors of Metabolism, Universidade Federal de 1–4 Sa˜o Paulo, Sa˜o Paulo, Brazil system microangiopathy, and/or positive family history, or 2 Center for Research and Molecular Diagnosis of Genetic Diseases, also families with high prevalence of kidney disease, cardio- Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil 1,2 myopathy, or ischemic encephalopathy. 3 Departament of Psychobiology, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, After diagnostic hypothesis of FD is raised, the diagnosis is Brazil made using laboratory testing. In males, the enzymatic activity Received October 09, 2016. Accepted for publication November 15, 2016. of a-gal A in plasma, leukocytes, skin biopsy, or dried blood spot (DBS) samples is measured. In females with clinical sus- Corresponding Author: Sandra O. Kyosen, Centro de Referenciaˆ em Erros Inatos do Metabolismo – picion, it is widely described in literature that there is a limita- CREIM, Rua Coronel Lisboa, Universidade Federal de Sa˜o Paulo, 957, CEP: tion in performing enzymatic activity assay, since women can 04020-041, Sa˜o Paulo, Brazil. range from almost undetectable, as can be found in males, up to Emails: [email protected]; [email protected] This article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Journal of Inborn Errors of Metabolism & Screening manifestations. Mutations known as ‘‘classic’’ have an earlier its metabolites (mainly lyso-Gb3) in urine/plasma and biopsies onset of symptoms, and usually cause a more severe clinical for histology/electron microscopy are also recommended.13 phenotype. On the other hand, ‘‘nonclassic’’ usually shows Lyso-Gb3 is similar to Gb3, only lacking the fatty acid slower disease progression with later onset of symptoms but chain.14 Levels of plasma lyso-Gb3 have been correlated with patients can also present severe organ damage.8 disease severity as well as with response to ERT.15,16 In male The treating physician has to be aware of the different kinds patients, lyso-Gb3 is a reliable diagnostic tool to distinguish of mutations and their clinical implications. Nonsense and fra- between classical and nonclassical FD from non-FD partici- meshift mutations are supposed to cause a severe phenotype, pants. However, in some cases of female patients, the levels since these mutations cause important damage to protein struc- of lyso-Gb3 overlap with controls, suggesting that increased ture (misfolding), leading to a highly dysfunctional protein.9 lyso-Gb3 values are very suggestive of FD, but normal values Mutations without previous description in literature require cannot exclude FD.17 Urinary lyso-Gb3 levels and its analogs further investigation not only by performing brain and heart are lower than plasma, but it has been demonstrated that male magnetic resonance imaging (MRI) but also by considering patients present higher levels of these markers when compared renal biopsy to evaluate which organs might be affected. There to females, and none of these markers are found in healthy are also controversial mutations, like the p.D313Y and intronic individuals.18 In addition, increases in lyso-Gb3/creatinine variants, described in literature as pathogenic by some ratio correlates with Gb3 concentration, types of GLA muta- authors10 and as benign by other authors.11 The treating phy- tion, gender, and ERT status,19 emphasizing the diagnostic sician should always rely on the patients’ clinical manifesta- value of this biomarker. tions and examination, rather than the genotype, when deciding whether to begin enzyme replacement therapy (ERT).12 Although there has been specific treatment over the last 15 Challenges in Biochemical Diagnosis years for FD, patients still face the challenge to have an early At our laboratory (LEIM-UNIFESP), DBS and leukocytes diagnosis that will allow a timely treatment initiation to avoid assays are performed to determine a-gal A activity through irreversible damage to organs. Treating physicians still have fluorometric methods using 4-methylumbelliferyl a-D-galacto- the challenge to decide what would be the ideal time to treat the pyranoside as substrate and a-N-acetylgalactosamine as later onset variants patients, and researchers of molecular a-galactosidase B inhibitor.20 These fluorometric assays are alterations face the challenge of the unknown effect of GLA the most commonly used for Fabry diagnosis, but the analysis variants. We will try to address some of these challenges. of a-gal A activity in DBS through tandem mass spectrometry has also become available.21–23 Since renal disease is a common feature among patients with Biochemical Diagnosis FD, individuals undergoing hemodialysis (with no other known diagnosis) have been considered a high-risk population for FD, Determination of a-gal A activity is usually the first laboratory with an overall prevalence of 0.62%, ranging from 0% to 1.2% test for diagnosing FD in index patients; if there is a known worldwide (reviewed by van der Tol et al).24 We performed a familial GLA mutation, a straightforward DNA analysis is indi- pilot screening protocol in which DBS samples from Brazilian cated. Many biological materials can be used for the analysis of hemodialysis centers were sent to LEIM-UNIFESP for a-gal A a-gal A activity, but the most common are plasma, leukocytes, activity analysis (this study was approved by the ethical fibroblasts, and DBS. The assay in leukocytes is regarded as the research committee from Universidade Federal de Sa˜o Paulo, ‘‘gold standard’’ and DBS assays are widely used for screening CEP #0384/05). We received 6277 DBS samples from male purposes. patients at hemodialysis centers located in all regions of Brazil, As an X-linked disorder, male patients can be reliably diag- and a-gal A activity was below the normal range in 320/6277 nosed with FD if presenting low or undetectable a-gal A activ- (5%) of samples. ity; results from DBS analysis below the normal range often As a primary screening protocol, patients with low a-gal A require a confirmatory test on leukocytes and, if low a-gal A activity in DBS were requested to send leukocyte samples to activity is also detected in this material, FD is confirmed. GLA confirm the diagnosis. From 320 patients with low enzyme sequencing for mutation identification is recommended for activity in DBS, only 176 (55%) actually sent new samples for index cases, which could provide important insights for prog- determination of a-gal A activity in leukocytes, probably due to nosis and treatment, as well as for genetic counseling but is not transportation issues, which is common in large countries like mandatory for diagnosis. Brazil—this type of sample must be transported under refrig- On the other hand, analysis of a-gal A activity in hetero- eration, in contrast to DBS, which can be transported at room zygous females is usually not conclusive for Fabry diagnosis, temperature or even sent by regular mail.
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